Clinical manifestations

Presentation and course

Wernicke encephalopathy. Wernicke encephalopathy manifests as decreased consciousness, ataxia, nystagmus, and ophthalmoparesis. Thiamine deficiency develops rapidly in those with intractable vomiting. In a single center series of 8735 autopsies performed over 5 years in Oslo, Wernicke encephalopathy was diagnosed in 70 cases (0.8%). Of these, 22 had acute and subacute presentation, and the rest were chronic (Korsakoff syndrome). Stupor and coma were the dominating symptoms in active cases (139). If seizures occur, EEG reveals generalized epileptogenic activity (106). Due to its various presentations, Wernicke encephalopathy may be confused with depression (130).

In a retrospective analysis, only 16% of 131 cases diagnosed by necropsy had the classical clinical triad documented (68). If untreated, Korsakoff syndrome may develop, characterized by severe anterograde and retrograde amnesia associated with confabulation in the initial stages. A disorientation of time is apparent. The emotional changes consist of apathy or mild euphoria, which respond little to various events (123). Additionally, executive function and emotion perception in others are impaired (08).

Cerebrovascular disease. All types of cerebrovascular disease, including transient ischemic attack, ischemic and hemorrhagic stroke, subarachnoid hemorrhage, dural sinus thrombosis, and cerebral venous thrombosis can occur during pregnancy and puerperium. Clinical presentation ranges from transient focal symptoms to coma and death. The neurologic deficits reflect the location of the insult hemiparesis, hemisensory loss, visual disturbances, neglect, aphasia, or alteration of awareness/coma. Headache and seizures can also occur.

Cerebral venous sinus thrombosis (CVST). Thrombosis of the deep cortical veins and cerebral venous sinuses occurs more often during pregnancy. Venous thrombosis is more often associated with headache (91%), seizures (39%), or increased intracranial pressure, including papilledema (28%), than arterial occlusion (30). Other symptoms include dizziness, nausea, focal neurologic symptoms, lethargy, and coma (19).

Subarachnoid hemorrhage. Subarachnoid hemorrhage is usually caused by a ruptured aneurysm. During preeclampsia, subarachnoid hemorrhage results from the rupture of the small pial veins (155). Subarachnoid hemorrhage may trigger vasospasm, even in absence of an aneurysm (53; 56). A patient who became rapidly comatose after subarachnoid hemorrhage recovered after cesarean section (26). Cortical vein thrombosis may result in infarction and subarachnoid hemorrhage (145).

Preeclampsia and eclampsia. Preeclampsia is defined as systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg measured on two occasions, at least 4 hours apart, associated with proteinuria developing after the twentieth week of pregnancy in a woman previously normotensive. If proteinuria is absent, preeclampsia is diagnosed as hypertension associated with new onset of any of the following: thrombocytopenia (< 100x9/L), elevated liver enzymes more than twice the normal concentration, elevation of creatinine more than twice normal or greater than 1.1 mg/dL in absence of other renal disease, pulmonary edema, new onset of unexplained headache, or visual disturbances. Preeclampsia with severe features occurs when systolic or diastolic pressures are greater than 160 or 110 mmHg, respectively, and preeclampsia is associated with end organ damage as described above. In this situation, the confirmatory measurement should be performed after a few minutes to expedite treatment (07).

The focal neurologic manifestations of preeclampsia reflect the location and size of the intracerebral hemorrhage, cerebral edema, and ischemic stroke caused by vasospasm (70; 145; 69). Carotid artery occlusion was described during rebound thrombocytosis of HELLP (83).

The visual symptoms are caused by retinal exudates, hemorrhages, edema, and/or retinal detachment. Cortical blindness has been attributed to microinfarcts and petechial hemorrhages in the visual cortex bilaterally. Symptoms can progress rapidly but generally resolve within 24 hours of delivery. Mortality typically results from large hematomas and severe cerebral edema (81).

Eclampsia occurs when seizures or coma develop in a patient with preeclampsia. Seizures are typically generalized tonic-clonic but may have focal or multifocal features (39). Eclampsia develops antepartum in 50% of patients, during labor in 25% and postpartum in 25%. Most postpartum seizures occur within the first 24 hours; however, they may appear as late as 26 days postpartum.

Posterior reversible encephalopathy syndrome (PRES). This syndrome is characterized by headache, encephalopathy, visual disturbances, and seizures associated with reversible vasogenic edema seen on CT or MRI. The syndrome resolves within 2 weeks (72). Posterior reversible encephalopathy syndrome often accompanies preeclampsia and eclampsia (104). In one center study, 46 of 47 patients (97.9%) with eclampsia had posterior reversible encephalopathy syndrome on neuroimaging (21).

Reversible cerebral vasoconstriction syndrome (RCVS). Patients usually present with multiple thunderclap headaches (reaching maximum intensity within 1 minute), seizures, confusion, visual changes, focal neurologic deficits, and coma. Cerebral vasculature imaging reveals vasoconstriction in at least two arteries that resolves within 3 months (24). Reversible cerebral vasoconstriction syndrome or postpartum angiopathy is sometimes associated with preeclampsia and mimics eclampsia if seizures occur (57).

Both PRES and RCVS may occur at the same time with preeclampsia (133). Whereas recurrent thunderclap headache is characteristic of RCVS, seizures are typical of PRES (128).

Hemolysis, elevated liver function, and low platelets syndrome (HELLP). This syndrome is also associated with preeclampsia. It presents as generalized edema, right upper quadrant or epigastric pain, nausea, and vomiting, which are typically worse at night (12). The neurologic presentations include seizures, neurologic deficits, and encephalopathy (116).

Prognosis and complications

Wernicke encephalopathy. Approximately 80% of untreated survivors of Wernicke encephalopathy related to alcohol abuse develop Korsakoff syndrome. The estimated mortality is 17% (144). Administration of 100 to 250 mg of thiamine daily may not prevent mortality, and up to 84% patients develop Korsakoff syndrome. More than 500 mg administered daily for several days is needed to increase the rate of recovery. In a small case series, complete resolution of symptoms occurred in 7 of 11 patients (111). A systematic review of the case studies, including 177 patients with hyperemesis gravidarum, found chronic cognitive impairment in 64.5%, a pregnancy loss of 50%, and maternal mortality of 5% of all cases. Thiamine supplementation was inadequate in 63.6% of cases (113).

Cerebrovascular disease. The Maternal Mortality Collaborative reported that 8.5% of deaths during pregnancy are related to stroke (05). Moreover, after a live pregnancy, 60% of women died from embolism and pregnancy-induced hypertension (27). Between 2006 and 2010, the proportion of deaths attributable to pregnancy-related conditions decreased, whereas the contribution of cardiovascular risk factors and infection increased (31). In the United Kingdom, the case fatality rate of all strokes was 20% and of hemorrhagic strokes was 50%. The mortality rate of stroke was 0.3 per 100,000 deliveries (122). In the United States between 2000 and 2001, the mortality rate from stroke was 1.4 per 100,000 deliveries (77). However, pregnant women with hemorrhagic stroke had fewer risk factors and better prognosis compared with nonpregnant women (95).

Intracerebral hemorrhage from aneurysm or arteriovenous malformation is responsible for up to 12% of all maternal deaths. Most hemorrhages (92%) occurred in the antepartum. Approximately 77% were caused by a ruptured aneurysm and 22% by arteriovenous malformation (37).

The mortality rate from subarachnoid hemorrhage was estimated at 27% to 40%, whereas the mortality rate from arteriovenous malformations was 28% (37). The prognosis is directly related to severity of neurologic grade at presentation of bleed (150). Data analysis from a National Inpatient Sample from 2010 to 2018 identified 13,351 patients with aneurysmal subarachnoid hemorrhage, of which 440 cases were in pregnant women (84). No difference in mortality or discharge to home was associated with aneurysmal subarachnoid hemorrhage. However, severity of hemorrhage, chronic hypertension, and small hospital were associated with higher mortality.

Cerebral venous sinus thrombosis (CVST). Historically, cerebral venous thrombosis has been associated with a high mortality rate; however, of the patients presenting with cerebral venous sinus thrombosis, 59% had modified Rankin scale (mRS) of 0 and 94% and had mRS of 0 to 2 at follow-up. Headache alone predicted an excellent outcome, whereas obtundation and coma predicted against excellent outcome (82). A multicenter observational study showed that patients with gender-specific risk factors (ie, pregnancy) had a rate of death/dependency of 12% compared with 20% in men and women without such risk factors (30). The cumulative risk of recurrence of thrombotic events, including CVST, is 6.5% (52).

Preeclampsia and eclampsia. Eclampsia causes approximately 60,000 maternal deaths per year worldwide (152). In the United States, the case fatality rate of preeclampsia-eclampsia is 6.4 per 10,000 cases at delivery and is twice as high in black compared to white women (102). Neonatal and maternal complications markedly increase when preeclampsia develops before 32 weeks’ gestation (125). Although most white matter lesions seen on brain MRI resolve, 40% of eclamptic women have persisting lesions at 7-year follow-up, compared to 17% of controls. Additionally, neurocognitive testing after preeclampsia or eclampsia revealed memory impairment (155). Furthermore, data from the Stroke Prevention in Young Women Study found a 60% increased risk of nonpregnancy-related ischemic stroke in women with a history of preeclampsia (23).

Posterior reversible encephalopathy syndrome (PRES). In a retrospective cohort of 70 patients with PRES, 94% had altered consciousness, 81% had seizures, and 14% had ischemic stroke or intracerebral hemorrhage. Most patients (56%) recovered at 90 days but 16% died and 37% had marked functional impairment (97).

Reversible cerebral vasoconstriction syndrome (RCVS). During the first week, cortical subarachnoid hemorrhage (22%), intracerebral hemorrhage (6%), seizures (3%), and reversible posterior leukoencephalopathy (9%) are diagnosed (42). Later, transient ischemic attacks (16%) and cerebral infarction (4%) are diagnosed. The outcome is death in 2% and severe neurologic sequelae in 9% of patients. However, most patients recover significantly within days to weeks (128). Recurrence is exceptional, although 5% can later develop isolated thunderclap headaches with or without mild cerebral vasoconstriction.

Hemolysis, elevated liver function, and low platelets syndrome (HELLP). The prognosis of HELLP is similar to that of severe preeclampsia except for the hematologic variables (65). A retrospective study of 12 patients with HELLP found neurologic complications in eight patients (66%): seizures, focal neurologic deficits, and encephalopathy. Six patients had radiologic evidence of PRES with or without hemorrhagic transformation and isolated intracerebral hemorrhage (116).

Clinical vignette

A 30-year-old primigravida presented at 39 weeks’ gestation with symptoms of early labor. She had no complications with pregnancy. Her only medication was low-dose aspirin for a remote history of a patent foramen ovale and transient visual symptoms. She delivered a healthy male infant with a forceps-assisted vaginal delivery. No symptoms of hypertension, edema, or proteinuria were noted. Approximately 6 hours postpartum, her blood pressure was 180/110 mm Hg and new proteinuria developed. She complained of chest pain and severe headaches. Within a few hours, she developed blurry vision in her right eye, ptosis, and lower extremity numbness. Subsequently, she had a generalized tonic-clonic seizure lasting 30 seconds. She was treated with intravenous diazepam and magnesium sulfate. Blood pressure responded to nitroglycerin.

Laboratory abnormalities were platelet count of 34,000, liver transaminases greater than 1600 mg/dl, prolonged prothrombin time, elevated creatinine, and hemolysis on peripheral blood smear. CT, MRI, and MR angiography showed a right frontal subarachnoid hemorrhage and diffuse cerebral edema. There was no venous thrombosis or arterial occlusion.

The headache and mental status worsened, requiring transfer to the neurointensive care unit. She received mannitol and dexamethasone. The seizures were treated, and her neurologic deficits resolved. Over the next 5 days, her laboratory abnormalities normalized.

This patient illustrates many aspects of severe eclampsia associated with HELLP syndrome. She had rapidly progressive neurologic symptoms in the early postpartum period. Symptoms resolved rapidly with aggressive treatment of hypertension, seizures, and cerebral edema.

Biological basis

Wernicke encephalopathy and Korsakoff syndrome. Central nervous system complications during pregnancy have multiple causes. Physiologic changes occurring during pregnancy include a relative hypercoagulable state, hormonal changes, and shifts in vascular volume.

Nausea and vomiting occur in approximately 70% of pregnant women. The more severe form, hyperemesis gravidarum, may affect 0.3% to 10.8% of pregnancies and leads to depletion of thiamine, a coenzyme essential for glucose metabolism. Etiology has a placental component by implicating common variants in genes encoding placental proteins and hormone receptors (50).

Thiamine deficiency triggers, particularly in Europeans, Wernicke encephalopathy and polyneuropathy or dry beriberi (18). This results in lactic acidosis and necrosis in the medial thalami, mammillary bodies, periaqueductal and paraventricular areas, locus coeruleus, cranial nerve nuclei, and superior cerebellar vermis (134).

The human body stores approximately 30 mg of thiamine and requires 1 to 2 mg of thiamine daily for the oxidative metabolism. The daily needs are increased by alcohol consumption (136). Moreover, the thiamine level may decrease in pregnant women despite multivitamin supplementation (10). Wernicke syndrome may be accelerated by prolonged administration of glucose infusion without thiamine (147).

A genetic susceptibility to develop thiamine deficiency on a diet limited in thiamine was described (123). Multiple humoral factors, from growth differentiation factor 15, insulin-like growth factor binding protein 7, glial cell line-derived neurogenic factor family receptor alpha-like receptor, to the progesterone receptor play a role in etiology of hyperemesis gravidarum (47).

Ischemic stroke. In pregnant women, ischemic stroke may be caused by the conditions unique to pregnancy and by the cerebrovascular risk factors present in the nonpregnant population.

The risk factors associated with pregnancy include peripartum cardiomyopathy, cerebral angiopathy, trophoblastic disease, preeclampsia, and eclampsia. A single-center retrospective study among women with pregnancy-associated stroke had fewer vascular risk factors. Most strokes occurred postpartum and were caused by cerebral venous thrombosis and reversible vasoconstriction syndrome (110).

Arterial occlusion caused by cardioembolism, arterial disease, and hematologic abnormalities is the major cause of ischemic stroke in pregnancy (40). The risk factors for stroke were age of 35 years and older, postpartum infection (odds ratio [OR] 25.0), African American race (OR 1.5), migraine (OR 16.9), thrombophilia (OR 16.0), systemic lupus erythematosus (OR 15.2), heart disease (OR 13.2), sickle cell disease (OR 9.1), hypertension (OR 6.1), preeclampsia and gestational hypertension (OR 4.4), postpartum hemorrhage (OR 1.8), transfusion (OR 10.3), and thrombocytopenia (OR 6.0) (77).

A systematic review of the literature from 1990 to 2022 found nine observational studies, of which eight were eligible for narrative synthesis. Of these, four studies that evaluated preeclampsia found a significant risk of atrial fibrillation. However, these studies were small and suffered from significant statistical heterogeneity (02).

Atherosclerosis accounts for 25% of stroke cases during pregnancy. Pregnancy may aggravate preexisting cardiac abnormalities (eg, valvular disease) or may cause new abnormalities (eg, peripartum cardiomyopathy). Arterial dissection, moyamoya, and Takayasu arteritis may be exacerbated by pregnancy. Rarely, stroke etiology includes air, fat, and amniotic fluid emboli (87). Retrospective analysis of 12 papers including 270 pregnant women with moyamoya disease has not detected an increased risk of stroke during pregnancy (54).

Inherited thrombophilias are associated with venous thromboses during pregnancy (59). Pregnancy is a hypercoagulable state. Increased levels of factors I, II, VII, VIII, IX, and XII and decreased levels of protein S and C have been documented. Moreover, the thrombolytic pathway is inhibited (20). Acquired procoagulant conditions include disseminated intravascular coagulation, sickle cell disease, thrombotic thrombocytopenic purpura, and antiphospholipid antibodies (138; 62). Clinical risk factors for peripartum and postpartum strokes include hypertension, cesarean delivery, and electrolyte and acid-base disorders (93).

Intracerebral hemorrhage. The main causes of intracerebral hemorrhage are hypertension, preeclampsia, or venous thrombosis. Congenital vascular abnormalities, such as aneurysms and arteriovenous malformations, can also cause intracerebral hemorrhage.

Cerebral venous sinus thrombosis (CVST). Venous occlusion is associated with dehydration, infection, and hyperviscosity and is often encountered during pregnancy. Antithrombin III deficiency, protein S and C deficiencies, and paroxysmal nocturnal hemoglobinuria are associated with venous infarction (40). Additionally, genetic mutations in the prothrombin, factor V Leiden, and methylenetetrahydrofolate reductase genes increase the risk of venous thromboembolism (59).

Preeclampsia and eclampsia. The mechanism of preeclampsia is complex and involves uterine vascular tone dysregulation due to endocrine dysfunction, immune system activation, and blood-brain barrier dissolution. Lately, genetic regulation has drawn more attention.

Preeclampsia and eclampsia result in loss of cerebral blood flow autoregulation, hyperperfusion, and edema (28). The increase in progesterone, human chorionic gonadotropin, and relaxin affect the cerebral vasculature (37). Additionally, excessive release of antiangiogenic factors by placenta like the soluble fms-like tyrosine kinase 1 and soluble endoglin was noted. This, coupled with reduced levels of proangiogenic factors like placental growth factor and vascular endothelial growth factor A, may explain the cerebrovascular manifestations (46). Other vasoactive agents involved in preeclampsia include nitric oxide, prostacyclin, thromboxane A₂, endothelin-1, and angiotensin II (60).

Alterations of the neutrophils, macrophages, lymphocytes, natural killer cells, inflammatory cytokines, and anti-angiotensin II type 1 receptor autoantibodies were described in association with preeclampsia (35). Neuroinflammation plays an important role, too. Women with preeclampsia have increased CSF levels of interleukin 6 and 8. Additionally, eclampsia is associated with an increased level of tumor necrosis factor alpha (16).

The blood-brain-barrier (BBB) permeability is also affected. The plasma concentrations of neuronal injury like neurofilament light (NfL), tau protein, neuron-specific enolase (NSE), and S100B were higher in women with preeclampsia than in women with normal pregnancies (55). In women with preeclampsia, neuron-specific enolase and S100B elevation persists at 1 year following delivery (15).

Maternal DNA analysis of 20,064 cases of preeclampsia and 11,027 cases of gestational hypertension found 18 loci associated with these two conditions (74). These loci underscore the role of trophoblast and vascular development, immune response, natriuretic peptide, and kidney function. A genome-wide association study of 16,743 women with prior preeclampsia and 15,200 with preeclampsia or other maternal hypertension during pregnancy found 19 loci related to blood pressure traits, renal function, placental development, remodeling of the uterine spiral arteries, and proteostasis in pregnancy serum (140). MicroRNAs are small molecules that regulate gene expression at the post-transcriptional level (71). Next generation sequencing revealed multiple alterations in microRNA expression that were associated with preeclampsia (107). These alterations have been proposed as potential markers for the diagnosis and monitoring of preeclampsia (131).

Posterior reversible leukoencephalopathy syndrome (PRES). This syndrome was observed mostly in patients with renal insufficiency, hypertension, or immunosuppression (72). The main pathogenic hypotheses are disturbance of autoregulation in cases of hypertension and endothelial dysfunction and blood-barrier disruption in cases of toxic agents. The predominantly posterior location may be explained by the less robust sympathetic innervation of the posterior circulation and a higher susceptibility for edema in the occipital lobes (58).

Reversible cerebral vasoconstriction syndrome (RCVS). Although the mechanism of RCVS is still unknown (127), the nature of the precipitating factors suggests excessive vasoconstriction triggered by cannabis, selective serotonin reuptake inhibitors, nasal decongestants, alcohol binging, steroids, ergots, triptans, cocaine, nicotine patches, noradrenergic and epinephrine, interferon alpha, cyclosporine, and sulprostone (33). There is an overlap between preeclampsia, RCVS, PRES, primary thunderclap headache, takotsubo cardiomyopathy, and transient global amnesia, suggesting some common pathogenic mechanisms (133; 141; 94; 127).

Epidemiology

Wernicke encephalopathy and Korsakoff syndrome. Out of 585 cases on nonalcoholic cases of Wernicke encephalopathy, most were due to hyperemesis gravidarum (177), cancer (129), and hunger strike (119) (114). Wernicke encephalopathy is diagnosed postmortem in up to 80% of cases (68). Approximately 80% of untreated or incompletely treated survivors with a history of alcohol related Wernicke encephalopathy develop Korsakoff syndrome characterized by severe memory impairment (144).

Ischemic stroke. Although rare, peripartum stroke was three times more frequent than in a young population of European descent in a study by Harmsen (67). Between 1955 and 1979, the likelihood of pregnancy-related stroke was 13 times higher than in nonpregnant women of a similar age (151). In New York State, the risk of stroke associated with pregnancy was increased in women younger than 35 years of age, but not in older women (108).

In the U.S., data from a nationwide sample found that stroke incidence was 34.2 per 100,000 deliveries (77). In England, an open-cohort study revealed an increased incidence rate of first ischemic and hemorrhagic stroke, both in peripartum and early postpartum. The incidence rate of stroke was 25.0 per 100,000 person-years outside pregnancy (11). A systematic review and meta-analysis that included 11 studies found that stroke affects 30 out of 100,000 pregnancies (132).

The stroke risk varies with the pregnancy stage. The relative risk of ischemic stroke adjusted for age and race was 0.7 during pregnancy but increased to 8.7 postpartum up to 6 weeks (86).

Discharge data from nonfederal emergency departments and acute care hospitals in California show a modestly increased risk of thrombotic events (stroke, myocardial infarction, or venous thromboembolism) between the seventh and twelfth week postpartum, but not beyond (80). In England, the rate was lower antepartum, 10.7 per 100,000 person-years, but increased 3-fold within 6 weeks to 47.1 per 100,000 person-years, and up to 9-fold to 161.1 per 100,000 person-years within 12 weeks from delivery (11).

The risk of recurrent strokes in subsequent pregnancies was less than 1% at 1 year and 2.3% at 5 years (92). There were 1.4 deaths per 100,000 deliveries (77).

Intraparenchymal and subarachnoid hemorrhage. The incidence rate of intracerebral hemorrhage is 3.5 to 4.6 per 100,000 deliveries. The adjusted relative risk was 2.5 during pregnancy, but it increased to 28.3 in the postpartum period. Overall, for both ischemic and hemorrhagic stroke during pregnancy and peripartum period, the adjusted relative risk was 2.4. The attributable, or excess, risk was 8.1 strokes per 100,000 pregnancies (86).

Subarachnoid hemorrhage occurs in 1 of 10,000 pregnancies but is five times more common in pregnant versus nonpregnant women (150).

Cerebral venous sinus thrombosis (CVST). A pooled analysis of 13 studies showed that the risk of pregnancy-related venous thrombosis and venous thromboembolism were low, 0.9% and 0.27%, respectively (06). Cerebral venous sinus thrombosis occurred in 10 to 20 per 100,000 births in North America and Europe but in up to 200 to 500 per 100,000 births in India. Most cases occurred during the second or third week postpartum (40; 93). The recurrence of cerebral venous thrombosis is 80-fold higher (0.9%) than the risk in the general population (06).

Pregnancy-related hypertensive disease. The incidence of gestational hypertension/preeclampsia is approximately 6% to 8% in the United States. The rate of preeclampsia is 2% to 7% in healthy nulliparous women; 14% in women with twin gestation; and 18% in women with prior preeclampsia (125). There appears to be a racial predisposition; 5% to 10% of whites and 15% to 20% of blacks are at risk. Other high-risk groups include new paternity, multiparous women older than 35 years of age with extrauterine pregnancy, hydatidiform mole, or multiple pregnancies (126; 81; 148). The incidence of eclampsia was 2.7 cases per 10,000 births in a population-based epidemiologic study in the United Kingdom in 2005, a nearly 50% reduction compared to data from 1992 (88).

Posterior reversible leukoencephalopathy (PRES). In the general population, the incidence is unknown. However, the incidence is 0.8% in end-stage renal disease, approximately 0.7% in systemic lupus erythematosus, and 0.5% in solid-organ transplantation survivors, but up to 98.0% among those with preeclampsia or eclampsia (58).

Hemolysis, elevated liver function, and low platelets syndrome (HELLP). HELLP syndrome occurs in 0.5% to 0.9% of all pregnancies and in 10% to 20% of those with severe preeclampsia. Most cases (70%) occur between 27 and 37 weeks and the remainder within 48 hours postpartum (66).

Prevention

Wernicke encephalopathy. Wernicke encephalopathy prevention consists of intravenous thiamine given to patients at risk. However, if urgently needed, glucose may be given before thiamine (64). In the absence of clinical trial data, urgent thiamine supplementation during or after glucose administration is recommended (121). Prompt administration of intravenous thiamine may also prevent Korsakoff syndrome, which responds little once developed. Intramuscular thiamine 250 mg should be administered daily to patients with poor nutritional status (135).

Ischemic stroke. Prevention of stroke during pregnancy should address the usual risk factors, in particular smoking.

Antiplatelets. For low risk of stroke, low-dose aspirin is recommended. In retrospective studies, aspirin was associated with gastroschisis during the first trimester (91). However, teratogenicity was not confirmed by prospective studies (13). Another concern is premature closure of the fetal ductus arteriosus and maternal or fetal hemorrhage. During the second and third trimesters, aspirin 150 mg or lower daily is safe (76).

Anticoagulation. Subcutaneous unfractionated heparin (UFH) or low molecular weight heparin (LMWH) is recommended for prevention and treatment of venous thromboembolism and of stroke in pregnant women with thrombophilia. Heparins do not cross the placenta and are not associated with teratogenicity or increased risk of fetal hemorrhage.

Low molecular weight heparin has a lower risk of osteoporosis and thrombocytopenia compared to unfractionated heparin (32). Low molecular weight heparin can be administered throughout pregnancy except for a minimum of 24 hours before the expected neuraxial anesthesia, induction of delivery, or C-section.

Warfarin crosses the placenta, is teratogenic during the first trimester, and increases the risk of fetal hemorrhage. Its use is limited to very high-risk cases, such as mechanical heart valve, or when the safety or efficacy of heparin is of concern. A discussion about the risks, benefits, and patient’s concerns is very important.

Patients with mechanical valves may benefit from one of the following regimens:

(a) Unfractionated heparin given subcutaneously every 12 hours and adjusted to keep mid-interval PTT at least twice the control level.

(b) Low molecular weight heparin adjusted to maintain the manufacturer’s peak anti-Xa heparin level 4 hours after the injection.

(c) Metallic mitral valve with higher risk for thrombosis, or additional history of thromboembolism, may benefit from unfractionated heparin or low molecular weight heparin until the thirteenth week, after which warfarin replaces heparin. Shortly before delivery, heparin can be resumed. If the fetal risk is deemed more concerning than valve thrombosis, heparin may be used instead of warfarin. Very high-risk patients may benefit from the addition of 75 to 100 mg of aspirin.

Women requiring long-term anticoagulation for other indications should be switched as soon as pregnancy is diagnosed to dose adjusted or 75% of therapeutic low molecular weight heparin for the duration of pregnancy.

The newer oral anticoagulants, such as direct thrombin inhibitors (eg, dabigatran) or anti-Xa (eg, rivaroxaban, apixaban) should be avoided (13).

Cerebral venous sinus thrombosis (CVST). The risk of recurrent CVST during a subsequent pregnancy is low. In a follow-up study of 112 women with a median follow-up of 14 years, 3 out of 82 new pregnancies experienced a venous thrombotic event, one of which was CVST (34). Nevertheless, low molecular weight heparin is recommended for women with a history of CVST (51).

Intraparenchymal hemorrhage. Pregnancy and puerperium do not increase the risk of hemorrhage in women with cavernous hemangioma (79) or aneurysm (137; 85). This suggests that pregnancy is not contraindicated or needs to be terminated when an incidental lesion is found. Unruptured arteriovenous malformations did not tend to bleed in one study (99) but bled more often in another (117). This conflicting data may reflect outcomes in different populations.

Subarachnoid hemorrhage. Current smoking and hypertension were associated with higher odds of being admitted with aneurysmal subarachnoid hemorrhage compared to treatment for unruptured aneurysm (146). Prevention of subarachnoid hemorrhage includes treatment of hypertension, avoidance of alcohol and tobacco, and a diet rich in fiber. Patients who had subarachnoid hemorrhage or whose first-degree relatives had subarachnoid bleeding should be noninvasively screened for undiagnosed or late regrowth of an aneurysm. After securing an aneurysm by clipping or coiling, follow-up imaging is performed to detect remnants or recurrence of an aneurysm that may require further management (73).

Preeclampsia and eclampsia. Screening for preeclampsia is recommended throughout pregnancy by monitoring the blood pressure (142).

Low dose aspirin is recommended throughout pregnancy starting from the second trimester (13). The number needed to treat (NNT) to prevent one case of eclampsia was 68 overall, though by separating out just the high-risk women, the NNT dropped to 18 (44).

Magnesium sulfate is superior to placebo or phenytoin at preventing seizures in women with preeclampsia (101; 29; 103). In a comparison study of women with severe preeclampsia, magnesium sulfate was more effective for seizure prophylaxis than nimodipine (14). The role of prophylactic magnesium sulfate in mild preeclampsia remains unclear (100; 125).

Differential diagnosis

Associated or underlying disorders

Considerable overlap exists between the clinical presentations of the various central nervous system complications described. Focal neurologic symptoms should prompt investigation for cerebrovascular disease (particularly venous thrombosis, arterial occlusion, or embolism) and intracerebral or subarachnoid hemorrhage. Space-occupying lesions such as tumors and infection from brain abscess, meningitis, and encephalitis can also cause symptoms.

The association of ataxia, ophthalmoparesis, and altered mental status in the context of malnutrition or prolonged vomiting suggests Wernicke encephalopathy. However, not all symptoms are present and often alcohol abuse is suspected.

Other causes for acute encephalopathy should be excluded. Among these are stroke (top of the basilar syndrome), paraneoplastic encephalitis, Bickerstaff encephalitis, Bechet disease, ventriculoencephalitis, Miller-Fischer syndrome, Leigh disease, variant Creutzfeldt-Jakob disease, as well as various toxic metabolic states (123).

Transient focal neurologic symptoms during pregnancy present a diagnostic challenge. In a case control series of patients with transient focal dysphasia, hemisensory loss or hemiparesis in the absence of migraine, recurrent thromboembolism, or known cerebral vascular disease, only 1 of the 14 patients had infarction on MRI DWI (98). Nine of the 14 patients had headaches of variable severity. None had abnormal MRV, echocardiogram, or carotid duplex ultrasonography, and none had a hypercoagulable state. No patients had recurrence of focal neurologic symptoms over a mean period of 12 months, although four patients developed recurrent migraine headaches.

Eclampsia may be difficult to diagnose when seizures and coma are preceded by minimal preeclamptic symptoms. Epilepsy must always be considered in the diagnosis of convulsions during pregnancy. Metabolic disorders like hypoglycemia, hypocalcemia, and water intoxication can also induce seizures and coma. Pheochromocytoma associated with fluctuating hypertension and hypertensive encephalopathy should also be excluded (81).

Preeclampsia with hematologic abnormalities should be differentiated from thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Thrombotic thrombocytopenic purpura is an idiopathic severe multisystem disorder, often precipitated by pregnancy. Clinical features include fever, hemolytic anemia, thrombocytopenic purpura, renal disease, and neurologic symptoms of stupor, coma, and convulsions (49). Hemolytic uremic syndrome is considered part of the same spectrum of disease, with similar clinical features. Both disorders are managed with plasma therapy and corticosteroids (149).

Diagnostic workup

Wernicke encephalopathy. The diagnosis of Wernicke encephalopathy is mainly based on clinical features. Thiamine level or red blood cell transketolase activity may confirm the initial suspicion (123). Cerebral MRI may reveal necrotic lesions in the regions associated with Wernicke encephalopathy: medial thalami, mammillary bodies, periaqueductal and paraventricular areas, locus coeruleus, cranial nerve nuclei, and superior cerebellar vermis (90; 09).

Acute ischemic stroke. Acute ischemic stroke requires evaluation for etiology in the young person (115). Complete blood count, sedimentation rate, syphilis screen, and coagulation studies should be performed. Testing for hypercoagulable states includes protein C and protein S levels, antithrombin III levels, and Russell viper venom test for antiphospholipid antibodies. Genetic screening includes Factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase mutations. Human chorionic gonadotropin level can be useful if choriocarcinoma is a suspected cause of hemorrhagic stroke (40).

CT scan with proper shielding can rapidly exclude intracerebral hemorrhage or evaluate for edema. MRI can assess focal brain pathology, acute ischemia, and cerebral edema. CT or MR angiography may demonstrate arterial stenosis, vasospasm, or occlusion. MR venography can detect cerebral venous thrombosis. If contrast agents are used, adequate hydration is recommended. CT perfusion can quantify the penumbra core mismatch and determine eligibility for thrombectomy in selected patients. Cardioembolism can be detected with EKG, loop recorder, and echocardiogram.

Subarachnoid hemorrhage. Lumbar puncture is essential for excluding subarachnoid hemorrhage but should be avoided if venous thrombosis with increased intracranial pressure is suspected (38). Advances in CT technology have improved the sensitivity for subarachnoid hemorrhage to 0.987 and specificity to 0.999 and may rule out hemorrhage within 6 hours from onset, without the need for lumbar puncture (41). Conventional cerebral angiography is useful for diagnosis of aneurysms and vasculitides.

Preeclampsia and eclampsia. If preeclampsia or eclampsia is suspected clinically, laboratory evaluation should include peripheral smear, hemolysis studies, and kidney and liver function tests. Reversible vasogenic edema resembling posterior reversible encephalopathy syndrome was demonstrated on brain CT and MRI (72). In a retrospective study of 49 women with preeclampsia and eclampsia with neurologic symptoms, 90% of patients with eclampsia and 20% of those with preeclampsia had MRI changes suggestive of posterior reversible encephalopathy syndrome (104).

Reversible cerebral vasoconstriction syndrome (RCVS). Initially, the brain CT is normal. Later, brain MRI may reveal convexity subarachnoid hemorrhage, lobar hemorrhages, and hyperintensities located in arterial "watershed" territories and reversible edema in up to 50% of patients (127).

Hemolysis, elevated liver function, and low platelets syndrome (HELLP). HELLP should be differentiated from acute fatty liver of pregnancy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura, which may present with similar clinical and laboratory findings (12). In addition to hemolysis, diagnosis of HELLP requires peripheral smear, elevated indirect bilirubin level, decreased haptoglobin level, and thrombocytopenia (124). In less than one third of patients, the diagnosis of HELLP syndrome is made based on specific laboratory abnormalities (81).

Management

Wernicke encephalopathy responds best to intravenous thiamine (68). Although no randomized trials are available, different regimens have been used: 500 mg intravenous over 30 minutes two to three times a day for 2 to 3 days or up to 6 days if no response is seen initially. If this regimen is effective, 250 mg intravenous or intramuscular is given daily for 5 days or until clinical improvement ceases. Moderate to severe nausea respond to pyridoxine-doxylamine, promethazine, metoclopramide, and ondansetron (105).

Ischemic stroke. Pregnant women were excluded from the randomized trials of stroke treatment. Alteplase or tPA is category C, does not cross placenta, and is not associated with animal teratogenicity. Off-label use of thrombolytics in 11 pregnancies (five intravenous and six intraarterial) resulted in one fatal intracerebral hemorrhage and three extracranial hematomas. Six fetuses were lost to abortion, three of which were elective (04). Analysis of Get With The Guidelines-Stroke registry data shows that nonpregnant women who received rt-PA had similar outcomes (96). It is reasonable to treat moderate or severe stroke with tPA if the benefit seems to outweigh the increased risk of uterine hemorrhage (118).

In the clinical trials that enrolled nonpregnant patients, large vessel occlusion is treated more effectively by endovascular treatment than intravenous rtPA alone (17; 25; 61; 78; 120). Perfusion imaging helps selection for endovascular intervention of patients presenting between 6 to 16 hours from the last time they were known to be normal (03). Even patients with stroke onset between 6 to 24 hours who exhibit a mismatch between the core delineated by MRI-DWI or CT perfusion and clinical severity may benefit from endovascular intervention (112). As endovascular treatment was not tested specifically in pregnant women, a thorough discussion of the risks and benefits as well as careful shielding are needed (22).

Cerebral venous sinus thrombosis (CVST). There are limited data on the best approach to CVST treatment. However, the consensus is that unfractionated or low molecular weight heparin is reasonable regardless of the presence of hemorrhagic transformation. If neurologic worsening occurs despite anticoagulation, or the mass effect or increased intracranial pressure is refractory to medical measures, surgical decompression or endovascular thrombolytic measures may be attempted (119).

Subarachnoid hemorrhage. Treatment of vascular malformations during pregnancy should be based on the same neurosurgical principles as in the nonpregnant state. Early aneurysm obliteration, but not the treatment of ruptured arteriovenous malformations, was associated with decreased mortality rate (37).

Labor and delivery do not appear to increase the risk of hemorrhage from arteriovenous malformations or aneurysms. The decision to perform caesarean section should be based on obstetric indications (75). The management of aneurysmal subarachnoid hemorrhage and arteriovenous malformations may require transfer to a specialized medical center (129). Increasingly, aneurysms are treated by endovascular approach, but the outcome is not modified by the treatment modality (84).

The definitive treatment of aneurysmal subarachnoid hemorrhage is obliteration of the aneurysm by coiling or clipping, ideally within 24 hours from onset. If there is a coagulopathy, it should be corrected. Until the aneurysm is secured, the systolic blood pressure should be controlled to prevent rebleeding while maintaining cerebral perfusion. There is no well-defined blood pressure target as this depends on multiple factors, like blood pressure on presentation, brain swelling, hydrocephalus, history of hypertension, or renal dysfunction. During anesthesia, it is important to control blood pressure and normoglycemia. After the ruptured aneurysm is obliterated, vaginal delivery is safe. If the ruptured aneurysm cannot be completely treated initially, partial obliteration and later retreatment may be attempted. Cesarean section is recommended in these patients (73). Surgical repair of the aneurysm immediately after delivery has been successfully performed (150; 39).

Vasospasm and delayed cerebral ischemia may be prevented by administration of oral nimodipine and intravenous fluids. Development of vasospasm is diagnosed with serial transcranial ultrasound, CT angiography, CT perfusion, or continuous EEG. Elevation of blood pressure with maintenance of euvolemia may be used in symptomatic ischemia. However, hemodynamic augmentation and hypervolemia should be avoided. If vasospasm and cerebral ischemia do not respond promptly to hydration, intra-arterial balloon angioplasty combined with a vasodilator may be needed to prevent stroke.

Seizures are diagnosed clinically and by EEG monitoring in patients with depressed or fluctuating consciousness. New-onset seizures should be treated. Prophylaxis is usually limited to 7 days. Longer-term prophylactic antiepileptic medication should be avoided but considered in patients at high risk, including rupture of middle cerebral artery aneurysm, high-grade subarachnoid hemorrhage, hydrocephalus, intraparenchymal hemorrhage, and cortical infarction (73).

Preeclampsia and eclampsia. The definitive treatment of preeclampsia and eclampsia is delivery (148). Control of hypertension, seizures, and management of cerebral edema may be needed. In severe cases, transfer to a neurointensive care unit, intubation, and hyperventilation may be necessary to manage cerebral edema. Mannitol should be used cautiously to avoid placental dehydration and pulmonary edema (81).

The management goal is prevention of cerebral and cardiovascular complications by lowering mean arterial pressure by 20% to 25%. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated during pregnancy. In a meta-analysis of antihypertensive therapy, early treatment decreased the frequency of hypertensive crisis and of neonatal complications. Labetalol and nifedipine were more effective and safer than hydralazine. Nimodipine, diazoxide, ketanserin, and magnesium sulphate are best avoided for hypertension treatment (45). After delivery, initiation of blood pressure control at a lower threshold (140/90 mmHg vs. 150/95 mmHg) did not seem to decrease maternal morbidity (01).

Seizures respond best to magnesium sulfate (29; 43; 103). Potential mechanisms include magnesium-induced vasodilation, protection of the blood-brain barrier resulting in decreased cerebral edema, or anticonvulsant activity mediated through NMDA receptor antagonism (48). Toxicity of magnesium includes profound weakness, hypoventilation, tocolysis, anesthetic complications, and neonatal weakness (39). Magnesium sulfate should be administered for prevention of seizures, with close monitoring of toxicity and serum levels of 4.2 to 8.4 mg/dL (48).

Posterior reversible leukoencephalopathy syndrome (PRES). Management of PRES is best undertaken in the neurologic ICU. The mainstay of treatment consists of removal of the provoking agent, treatment of high blood pressure, seizures, cerebral edema, and encephalopathy. Urgent decrease of systolic blood pressure up to 25% is followed by normalization of blood pressure within 24 to 48 hours. Nicardipine, clevidipine, or labetalol intravenously are the preferred agents. Seizures should be treated with a benzodiazepine followed by a longer acting antiepileptic (58).

Reversible cerebral vasoconstriction syndrome (RCVS). Once diagnosed, avoid the triggering factors and glucocorticoids. Vasodilation with oral calcium-channel blockers is used for reversal of the arterial spasm. In refractory cases, intra-arterial vasodilators can be used (127). In case reports, Cesarean section with general or epidural anesthesia resolved the headache promptly (36; 154).

Hemolysis, elevated liver function, and low platelets syndrome (HELLP). Conservative treatment is controversial and may be attempted in partial cases before 34 weeks’ gestation. Between 24 and 34 weeks, corticosteroid therapy is needed for fetal lung maturation (66). Delivery is indicated after 34 weeks or if the clinical condition of the mother or fetus deteriorates. A Cochrane review did not support the use of corticosteroids in HELLP syndrome (153).

Special considerations

Anesthesia

In patients with ischemic or hemorrhagic stroke, neuraxial analgesia and anesthesia are generally safer than general anesthesia. Unless cesarean is required for obstetrical reasons, vaginal delivery is preferred. Therapeutic anticoagulation or increased intracranial pressure are indications for cesarean delivery, in which case, general anesthesia is preferred (109).